PI3K is a lipid kinase and can phosphorylate 3-position of inositol ring in phosphatidylinositol to form phosphatidylinositol-3-phosphate (PIP), phosphatidylinositol-3,4-diphosphate (PIP2) and phosphatidylinositol-3,4,5-triphosphate (PIP3). PIP, PIP2 and PIP3, as important second messengers, bind and activate various proteins containing PH domain (pleckstrin homology domain), FYVE domain (named after the first letter of Fablp, YOTB, Vaclp and EEA1 proteins containing FYVE domain found originally, see Gaullier, J. M.; Simonsen, A.; D'Arrigo, A.; Bremnes, B.; Stenmark, H., Chem. Phys. Lipids, 1999, 98: 87-94.), PX domain (Phox homology domain) and other phospholipid-binding region, to form a signaling cascade complex, and ultimately regulate cell activities such as proliferation, differentiation, survival and migration etc. (see Vanhaesebroeck, B.; Leevers, S. J.; Ahmadi, K.; Timms, J.; Katso, R.; Driscoll, P. C.; Woscholski, R.; Parker, P. J.; Waterfield, M. D., Annu. Rev. Biochem., 2001, 70: 535-602).
Depending on the differences in gene sequence, the substrate specificity and function, PI3K superfamily is grouped into three classes: I, II and III PI3K. Class I PI3Ks are most widely studied class by far. The substrates of PI3Ks are phosphatidylinositol (PI), phosphatidylinositol-4-phosphate (PI(4)P), phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). Class I PI3Ks are heterodimeric molecules composed of one catalytic subunit and one regulatory subunit. Class I PI3Ks can be further divided into two categories due to the difference in the regulatory subunit and activation mechanism: PI3K IA and PI3K IB. Wherein, PI3K IA comprises PI3Kα, PI3Kβ and PI3Kδ, and is actived by receptor tyrosine kinase; while PI3K IB only consists of PI3Kγ and is actived by G protein-coupled receptors. PI and PI(4)P are substrates of class II PI3Ks. Class II PI3Ks include PI3KC2α, PI3KC2β and PI3KC2γ. They are characterized by a C2 domain at the C terminus, indicating that their activities are regulated by calcium ion. The substrate of class III PI3K is PI. Its activation mechanism remains unclear up to now (see, Engelman, J. A.; Luo, J.; Cantley, L. C., Nat. Rev. Genet., 2006, 7: 606-619).
Hyper-activation of PI3K initiates phosphatidylinositol 3-kinase/protein kinase B/mammalian target protein of rapamycin (PI3K/Akt/mTOR) signal pathway and promotes cell survival and proliferation, which is frequently present in about 60% of human tumors. PTEN (phosphatase and tensin homolog deleted on chromosome 10) acts as a tumor suppressor and dephosphorylate 3-position at inositol ring of phosphatidylinositol and antagonize the activity of PI3K. Such function is lost in many cancers. Active mutation in gene PIK3CA encoding p110α is present in over 30% of cancers. Moreover, gene amplifications of PI3K3CA and protein kinase B (Akt) have been frequently found in other cancers which also contribute to the expression of protein (see Engelman, J. A., Nat. Rev. Cancer, 2009, 9: 550-562). These facts indicate that PI3K is closely related to the tumorigenesis and promotion. The target protein of rapamycin (mTOR) is one of important downstream protein of protein kinase B, which is a serine/threonine kinase. Protein kinase B further activates the target protein of rapamycin by directly phosphorylating mTOR; or indirectly enhancing the activation of mTOR by inactivating tumor suppressor gene TSC2 (Tuberous sclerosis protein 2). The active mTOR directly or indirectly takes part in regulations of various processes relating to cell proliferation and growth, such as the initial stage of translation, transcription, microfilament restruction, membrane transport, protein degradation, protein kinase C (PKC) pathway, ribosomal protein synthesis and tRNA synthesis etc by regulating downstream signaling pathways, such as ribosome S6 kinase (S6K1, or P70S6K), eukaryotic cells translation initiation factor 4E (eIF-4 e) binding protein 1 (4E-BP1), signal transduction and transcription activation factor 3 (STAT3), etc. Therefore, mTOR is a center regulatory protein of cell growth and proliferation and has become a new antitumor drug target.
PI3K and downstream signaling protein mTOR inhibitors are a class of promising antitumor drugs. At present, several pan-PI3K inhibitors, such as GDC-0941, XL-147, PX-866, etc. have entered into clinical studies. However, the number and structure diversity need to be expanded to meet the needs of research and development of new anticancer drug. Meanwhile, there are defects existing in known inhibitors. For example, PX-866, which is derived from Wortmannin, is difficult to be synthesized; and the activity of GDC-0941 needs to be improved. Therefore, discovery and development of antitumor drugs targeting PI3K with higher activity, better safety attract increasing interest world wide.
Pyrrolo[2,1-f][1,2,4]triazine is a privileged structure in medicinal chemistry. After this privileged structure was reported as purine analogues (see: Hayashi, M.; Araki, A.; Maeba, I., Heterocycles, 1992, 34: 569-574. Patil, S. A.; Otter, B. A.; Klein, R. S., Tetrahedron Lett., 1994, 35: 5339-5342), more and more compounds containing such privileged structure were synthesized and displayed a variety of biological activities, for example, acting as JAK2 inhibitors (see: Weinberg, L. R.; Albom, M. S.; Angeles, T. S. et al., Bioorg. Med. Chem. Lett. 2001, 21: 7325-7330), pan-Aurora kinase inhibitors (Abraham, S.; Hadd, M. J.; Tran, L. et al., Bioorg. Med. Chem. Lett. 2011, 21: 5296-5300), p38α mitogen-activated protein kinase (p38a MAPK) inhibitors (Liu, C.; Lin, J.; Wrobleski, S. T. et al., J. Med. Chem., 2010, 53: 6629-6639), lymphoma kinase ALK inhibitors (Mesaros, E. F.; Thieu, T. V.; Wells, G. J. et al., J. Med. Chem., 2012, 55: 115-125), VEGFR-2/FGFR-1 dual inhibitors (Cai, Z.-w.; Zhang, Y.; Borzilleri, R. M. et al., J. Med. Chem., 2008, 5: 1976-1980), VEGFR-2 inhibitors (Hunt, J. T.; Mitt, T.; Borzilleri, R. et al., J. Med. Chem., 2004, 47: 4054-4059), EGFR1/2 inhibitors (Gavai, A. V.; Fink, B. E.; Fairfax, D. J. et al., J. Med. Chem., 2009, 52: 6527-6530), IGF-1R inhibitors (see: Wittman, M. D.; Carboni, J. M.; Yang, Z. et al. J. Med. Chem., 2009, 52: 7360-7363), or Met kinase inhibitors (see: Schroeder, G. M.; Chen, X.-T.; Williams, D. K. et al., Bioorg. Med. Chem. Lett., 2007, 18: 1945-1951). Moreover, compounds containing this pyrrolo[2,1-f][1,2,4]triazine privileged structure such as EGFR inhibitor AC-480 (WO-2004054514), VEGF-2 receptor antagonist BMS-690514 (WO2005/066176A1), and IGF-1R antagonist BMS-754807 (US2008/0009497 A1) etc. have entered into the clinical studies. The synthetic methods for the core structure of pyrrolo[2,1-f][1,2,4]triazine have also been reported, for example, Thieu, T; Sclafani, J. A.; Levy, D. V. et al., Org. Lett., 2011, 13: 4204-4207. In addition to above mentioned literatures, there are many patent applications related to the core structure of pyrrolo[2,1-f][1,2,4]triazine, for example, acting as kinase inhibitors (publication No.: US2006/0084650A1), EGFR kinase inhibitors (Publication No.: US2006/0089358A1, WO2006/069395), VEGFR-2 and FGFR-1 inhibitors (Publication No.: WO2004/009784, WO2004/043912), and patent applications related to the synthetic methods for intermediates (WO2007/005709, WO2008/083398), tyrosine receptor kinase inhibitors (WO2007/061882, WO2008/131050), Aurora kinase inhibitors (Publication Number: WO2009/136966), JAK kinase inhibitors (Publication No.: WO2010/002472). The reported pyrrolo[2,1-f][1,2,4]triazines mentioned above do not cover and relate to the compounds of the present invention and use thereof as PI3K inhibitors.
Based on the aforementioned reasons, the inventors designed and synthesized a series of PI3K inhibitors with pyrrole[2,1-f][1,2,4]triazine as core structure. The compounds in the present invention have demonstrated excellent bioactivity both in vitro and in vivo, and are expected to be developed into a novel anti-cancer medicament.